CN1294121A - N-acyl amino-acid amide prodn. process - Google Patents
N-acyl amino-acid amide prodn. process Download PDFInfo
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- CN1294121A CN1294121A CN00131480A CN00131480A CN1294121A CN 1294121 A CN1294121 A CN 1294121A CN 00131480 A CN00131480 A CN 00131480A CN 00131480 A CN00131480 A CN 00131480A CN 1294121 A CN1294121 A CN 1294121A
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Abstract
There is provided a process for producing an N-acyl amino acid amide, comprising a condensation reaction of an N-acyl amino acid with an amine and/or an ammonia, preferably a primary amine, a secondary amine and/or an ammonia under dehydration in the presence of a boron compound as the catalyst under coexistence of an alcohol as the auxiliary solvent, at a high yield for a short time. A medium for hylotropic dehydration such as hydrocarbon compounds may be used in the reaction.
Description
The present invention relates to produce improving one's methods of N-acyl amino-acid amide.
The N-acyl amino-acid amide has many application, and as antioxidant, cosmetics additive, static inhibitor and as the antiseptic-germicide of oily molten nonionogenic tenside, described N-amino acid amide toxicity is low, little and biodegradability is good to skin irritation.In addition, the N-amino acid amide can at room temperature solidify organic medium liquid, particularly inflammable organic medium, as natural or synthetic mineral is oily and vegetable and animals oils, and do not fire the organo phosphorous compounds organochlorine compound, this compounds is gel, agar gel shape or bulk (referring to Japanese Patent Laid open JP-B-51-42079, JP-B-53-13434 and JP-B-53-27776), this shows that its industrial application value in gelatinizing agent is very remarkable and considerable.
For the method for producing the N-amino acid amide, following method is known: the carboxyl in the N-acylamino acid is transformed into the active group of hyperergy, as in ester, is transformed into carboxylic acid halides and acid anhydrides, its derivative with gained reacts with amine then; Under dehydration conditions, the N-acylamino acid is heated with amine, directly form acid amides; Or the like.
For the N-acylamino acid being transformed into the active carboxylic acid derivative that carboxyl wherein has been transformed into the active group of hyperergy; existing many descriptions in the document; therefore; by considering as the activity of the N-acylamino acid of starting raw material and the stability of gained derivative; can select suitable derivatives; further, in order to produce target N-acyl amino-acid amide, should under high yield condition, obtain the active carboxylic acid derivative of reaction intermediate.For example; by between N-acylamino acid and alcohol, carrying out dehydration condensation; can produce the N-acyl amino acid ester; but in order to obtain high yield N-acyl amino acid ester; because reaction is typical balanced reaction; therefore must be by using much excessive alcohol immediately and removing the modes such as water that generate in the dereaction, the balance of shift reaction.For one of them embodiment, the method that quantitatively obtains N-lauroyl-L-glutamic acid dimethyl ester in the reaction of N-lauroyl-L-L-glutamic acid and methyl alcohol is known (referring to Japanese patent gazette JP-A-9-221461), and there is acid catalyst in wherein said being reflected at and uses trimethyl orthoformate as carrying out under the condition of dewatering agent; In addition, the method by ester-amide exchange reaction production N-lauroyl-L-L-glutamic acid di-n-butyl acid amides also is known (referring to Japanese patent gazette JP-A-10-001463) in the reaction of N-lauroyl-L-glutamic acid dimethyl ester and n-Butyl Amine 99.In the described method of active therein N-acyl amino acid derivative as the generation of the reaction intermediate in the reaction scheme, reaction is under general condition carried out, and has obtained good yield.But, the reactions steps of this reaction is a lot, complex operation, so compare with the method (directly amidation method) of direct generation acid amides, have deficiency on productive rate, its reason is to remove unnecessary reaction solvent and the dewatering agent that is used to produce reaction intermediate before carrying out amidation method.In addition, in order successfully to carry out amidate action, every 1mol ester must use 3 to 6mol excess amines.
As the embodiment that removes the direct amidation method that anhydrates by heating N-acylamino acid and amine; the N-acylamino acid that has a carboxyl groups that contains 1 to 22 carbon atom by direct heating is known (the open JP-B-52-18691 of Japanese Patent Laid) with containing 8 or the alkylamine of more a plurality of carbon atoms and the method that makes its reaction obtain the N-acyl amino-acid amide, is to contain 7 or less than the situation of the alkylamine or the ammonia of 7 carbon atoms but this method is difficult to be applied to alkylamine.That is to say; the known method of this class is corresponding to the method that obtains target N-acyl amino-acid amide; this method comprises: the N-acylamino acid is mixed with the amine that contains 8 or 8 above carbon atoms; under 160 to 200 ℃ of temperature, directly be heated; or anhydrate (dehydration) existing under inert solvent (as the dimethylbenzene) condition its reflux removed, still this method has more following weakness (shortcoming).When this method being applied to contain 7 or during less than the alkylamine of 7 carbon atoms, because the boiling point of amine is low, so under 160 to 200 ℃ the direct heating condition or exist under the heating condition of dimethylbenzene etc., amine can vapor away, the yield of reaction is low.And the amino acid residue in the N-acylamino acid is in the acidic amino acid state and has under the situation of a plurality of (two or more) carboxyl therein, and one of them carboxyl is easy to react and the lower trend of another carboxyl-reactive is tangible.Thus, in order to obtain two-or three-acid amides substitutive derivative, they must react temperature of reaction height, long reaction time under the condition of harsh (strictness).Under this reaction conditions, the condensation reaction between target carboxyl and amine, also can generate side reaction, as the oxidizing reaction of amine, under condensation between N-acyl group and the amine permutoid reaction and generate nitrile, cause the generation of by product.Moreover, optically active N-acylamino acid is being used as under the situation of starting raw material, owing to produce racemization simultaneously, therefore may cause can not get problems such as target optically active N-acyl amino-acid amide.
In order to overcome above-mentioned shortcoming (weakness), in the method for utilizing the direct amidation N-of secondary amine or ammonia acylamino acid, the wherein common method (referring to Japanese patent gazette JP-A-61-00050) that exists as the boron compound of catalyzer in reaction is disclosed.With the reacting phase ratio that does not have catalyzer, by using the catalyzer of coexistence, reaction can be carried out at low temperatures and can obtain required (target) product by high yield.In addition, because reaction carries out at low temperatures,, also can obtain racemization is controlled at effect on very low-level even use optically active N-acylamino acid as starting raw material.But, it is water-soluble to be used for catalyst for reaction, so do not have medium or when in carbohydrate (described carbohydrate is azeotropic (azeotropic) dehydration medium or its coexistence mixture), carrying out when being reflected at, catalyzer can not dissolve fully, can not obtain homogeneous reaction system, insoluble catalyst deposit is on the inwall of reactor, and squamous is assembled formation bumping etc.Also have a problem in addition, reaction can not be accelerated, thus the reaction times just can not shorten, this is that catalyst efficiency reduces, and the catalytic amount that joins wherein is limited because insoluble catalyzer can not participate in reaction.Moreover according to aforesaid method, in the reaction of N-acylamino acid and secondary amine, the reactivity of secondary amine can not sufficiently be accelerated, and therefore reaction can not successfully be carried out.Thus, the yield of acquisition N-acyl amino-acid amide can not be satisfactory.
1, the problem of the present invention's solution
Under the background condition of above-mentioned correlation technique, problem to be solved by this invention is to develop a kind of method of the N-of production acyl amino-acid amide, and this method comprises the step that N-acylamino acid and primary amine, secondary amine or ammonia are directly reacted.The present invention has developed improving one's methods of dealing with problems in process of production, described problem comprises the deposition (squamous of catalyzer is assembled) as catalyzer etc., in addition, described improving one's methods can be improved the efficient of catalyzer, feasible reaction is carried out at short notice and in the identical time, is obtained target product with good yield.
The mode of 2, dealing with problems
In order to deal with problems; the present inventor concentrates on studies; found that: by common exist as the boron compound of catalyzer and condition as the alcohol of solubility promoter under; with N-acylamino acid and primary amine; secondary amine or ammonia react; even carbohydrate or its mixture at the medium that dewaters as azeotropic (azeotropic) exist or do not exist under the condition of azeotropic dehydration medium (carbohydrate or its mixture); reaction system can be made homogeneous phase; can improve the problem in the production method thus; for example, can suppress the squamous of catalyzer on reactor wall assembles.In addition, they find, compare as the system of catalyzer (not using solubility promoter) with independent use boron compound; by in reaction system, catalyzer being made homogeneous phase; the efficient of catalyzer can improve, and makes reaction quicken, and promptly can obtain the N-acyl amino-acid amide by high yield at short notice.
Above-mentioned discovery has just caused of the present invention finishing.
That is to say; in the method for producing the N-acyl amino-acid amide; this method comprises carries out dehydration condensation with N-acylamino acid and amine and/or ammonia; the wherein preferred primary amine of amine and/or ammonia, secondary amine or ammonia; the present invention relates to it and improve one's methods, wherein said condensation reaction is carried out under existing as the boron compound of catalyzer and the condition as the alcohol of solubility promoter common.The N-acylamino acid can be a salt form.
The invention still further relates to the method for producing the N-acyl amino-acid amide; this method is included in common existence as under the boron compound of catalyzer and the condition as at least a alcohol of solubility promoter; N-acylamino acid and amine and/or ammonia are carried out dehydration condensation, wherein the preferred primary amine of amine and/or ammonia, secondary amine or ammonia.The N-acylamino acid can be a salt form.
In the present invention, condensation reaction is preferably carried out under acidic conditions.In this case, the N-acylamino acid can be a free form.
The preferred embodiment of the invention
For the method for producing the N-acyl amino-acid amide; this method comprises carries out dehydration condensation with N-acylamino acid and primary amine, secondary amine or ammonia, and described method has adopted known method, known approaches, well-known operations condition and other other condition of having developed etc. under the condition of not using the solubility promoter that constitutes as the present invention.Thus, all relate to the content of publication of N-acylamino acid and primary amine, secondary amine or ammonia being carried out dehydration reaction and producing the method for N-acyl amino-acid amide and are hereby incorporated by reference.
For for the amino acid of the composition that constitutes the N-acylamino acid that is used as starting raw material of the present invention; can use any acidic amino acid, neutral amino acids and basic aminoacids; also can use any a-amino acid, beta-amino acids and epsilon-amino acid; for example Padil, Beta-alanine, α-Bing Ansuan, Xie Ansuan, L-LEU, phenylalanine, 3,4-dioxy base L-Ala, Serine, Threonine, methionine(Met), Methionin, ornithine, arginine, Histidine, epsilon-amino caproic acid, L-glutamic acid, aspartic acid etc.The N-acylamino acid can be a salt form, as using N-acyl glutamic acid disodium salt, N-acyl glutamic acid one sodium salt etc.In these salt, owing to single salt can obtain easily, so preferred single salt.In the present invention, hereinafter described the N-acylamino acid comprises its salt form.
For for the acyl group of the composition that constitutes its carboxyl groups, can use saturated or unsaturated fatty acids deutero-acyl group by the straight or branched that contains 1 to 30 carbon atom.For example, can use acyl group, as formyl radical, ethanoyl, propionyl, caproyl, capryloyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearyl-, mountain Yu alkynes acyl group, oleoyl, inferior oleoyl by single fatty acid derived; And by natural mixed fatty acid deutero-acyl group, as by coco-nut oil fatty acid deutero-acyl group, by acyl group of hardened tallow fatty acid derived or the like; Also can use in addition by aromatic carboxylic acid's deutero-acyl group, as by phenylformic acid deutero-acyl group etc.Certainly, acyl group also can be by many material derived except can be by this class fatty acid derived.
For under heating condition with the amine of N-acyl amino acid-respons, can enumerate saturated or unsaturated primary amine of the straight or branched that contains 1 to 60 carbon atom and secondary amine, comprise one-or two-hydramine, aromatic amine, aliphatic amine etc.For example, can use methylamine, ethamine, propylamine, butylamine, hexylamine, octylame, 2 ethyl hexylamine, lauryl amine, hexadecyl amine, stearic amine, cyclopentamine, hexahydroaniline, 4-sec.-propyl hexahydroaniline, aniline, benzene methanamine, naphthylamines, 4-isopropyl aniline, dimethylamine, N-thyl methyl amine, diethylamine, di-n-propylamine, Di-n-Butyl Amine, N methyl butylamine, piperidines, 3,5-lupetidine, N-methyl lauryl amine, dilaurylamine, distearyl amine, N-methyl benzene methanamine, monoethanolamine, diethanolamine etc.
For the boron compound as catalyzer, ortho-boric acid, metaboric acid, pyroboric acid and boron oxide etc. all are fit to, and the present invention can use and be selected from above-mentioned any compound or several combination of compounds.In addition, the present invention does not refuse following any situation: borate can in and form use with mineral acid, described borate comprises borax (pyroborate), ammonium borate (ammonium pentaborate) etc., described mineral acid comprises sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid etc.
For for the alcohol of the coexistence solubility promoter of reaction system, it is saturated or unsaturated aliphatic is pure (Fatty Alcohol(C12-C14 and C12-C18)), contain the saturated or unsaturated cyclic alcohol of 3 to 8 carbon atoms, saturated or unsaturated alkyl ether alcohol (comprising alkene ether alcohol etc.) etc. all is suitable for to contain the straight or branched of 3 to 8 carbon atoms.
Saturated or unsaturated aliphatic is pure for the straight or branched that contains 3 to 8 carbon atoms, can use especially as 1-propyl alcohol, 2-propyl alcohol, 1-butanols, 2-butanols, 2-methyl isophthalic acid-propyl alcohol, the trimethyl carbinol, 1-amylalcohol, 2-methyl-1-butene alcohol, 4-methyl isophthalic acid-butanols, 2-methyl-2-butanols, 1-hexanol, 1-enanthol, 1-octanol, 2-Ethylhexyl Alcohol, allyl alcohol, crotyl alcohol, methyl ethylene methyl alcohol etc.Can use cyclopentanol, hexalin etc. for the saturated or unsaturated cyclic alcohol that contains 3 to 8 carbon atoms.For saturated or unsaturated alkyl ether alcohol, can use compound as following general formula (1) expression:
R
1-O-R
2-OH (1) is R wherein
1Expression contains the straight or branched alkyl or the unsaturated alkyl (comprising alkenyl etc.) of 1 to 4 carbon atom, R
2Expression contains the straight or branched alkyl of 2 to 5 carbon atoms; Particularly 2-methyl cellosolve, cellosolvo, 2-propoxy-ethanol, 2-isopropoxide ethanol, butoxy ethanol, 1-methoxyl group-2-propyl alcohol, 1-oxyethyl group-2-propyl alcohol, 3-oxyethyl group-1-propyl alcohol, 1-propoxy--2-propyl alcohol, 1-tert.-butoxy-2-propyl alcohol, 1-methoxyl group-2-butanols, 3-methoxyl group-1-butanols, 3-methoxyl group-3-methyl isophthalic acid-butanols, ethylene glycol vinyl ether, ethylene glycol allyl ethers, propylene glycol vinyl ether, propylene glycol allyl ethers etc.The present invention can use the independent compound that is selected from above-mentioned alcohol or use its several compounds.
Be not to exist jointly under the situation of solubility promoter in reaction system, because the boron compound catalyzer can not dissolve fully, so reaction system is heterogeneous, and reaction efficiency is low, and in addition, insoluble catalyzer is deposited on the inwall of reactor with the squamous aggregated forms.Consequently, particularly at the commitment of reaction, the dehydrating amount that generates in the condensation reaction is more, causes bumping, foaming (foaming) etc., and this is because it demonstrates the trend that viscosity increases.
On the other hand, under solubility promoter and the common situation about existing as the boron compound of catalyzer, reaction system can be made into homogeneous phase, thereby improves reaction efficiency.Moreover; compare with the situation of only using the boron compound catalyzer; for accelerated reaction significantly, shortening reaction times; can increase adding catalyzer amount in addition; N-acylamino acid and heat-labile amine can not cause side reaction (as decomposition reaction); required dehydration reaction can be carried out, so target N-acyl amino-acid amide can obtain by high yield.Also have, do not assemble, therefore do not worry in process of production bumping, foaming etc. owing on the inwall of reactor, do not produce the catalyzer squamous.Even optically active N-acylamino acid also can be used as starting raw material, reaction can be finished in temperature is approximately 110 to 125 ℃ of following short period of time, racemization can not take place, and can obtain target optically active N-acyl amino-acid amide thus.
Implementing when of the present invention, N-acylamino acid and amine or ammonia can exist jointly, and to wherein adding small amount of boron compound and solubility promoter, the gained mixture can heat in the presence of azeotropic (azeotropic) dehydration medium or heat not existing under the azeotropic dehydration medium.Thus, be easy to reacting this operation.Certainly, add solubility promoter, other solvent does not produce ill effect to the present invention, can use the present invention, can not use the azeotropic dehydration medium yet.
Thus, for being used for medium of the present invention, solubility promoter is substantial, and the azeotropic dehydration medium can use, and also can not use, and other solvent mentioned above can use, and also can not use.
As for as the N-acylamino acid of starting raw material and the ratio of amine, can not have under the condition of further particular determination, in the carboxylic group of per 1 equivalent N-acylamino acid, use 1.0 equivalent amine or use more amine; Certainly, the carboxylic group of per 1 equivalent N-acylamino acid preferably uses 1.0 to 3.0, more preferably 1.0 to 1.5 equivalent amine.That is to say that for the amine that consumes in the reaction, 1 equivalent amine is equivalent to 1 equivalent carboxyl, but, carry out in the process in reaction, because the density loss of unhindered amina, long for fear of the reaction deadline, can be in having the scope of economic advantages, the excessive a little amine of preferred use.At amine is under any in methylamine, the ethamine etc. and the situation that ammonia can participate in reacting; because any in these amine or the ammonia all is low-boiling point materials; this material volatilizees from reaction system under heating easily, so preferably increase the equivalent ratio as the amine or the ammonia of starting raw material in the carboxyl of the N-of unit acylamino acid.That is to say, preferably carry out compensating gaseous state amine or ammonia in the process bit by bit in reaction, make the equivalent ratio of this class low-boiling amine in the unit residue carboxyl in the reaction system or ammonia remain on 1.0 or more than.
The add-on that is used as the boron compound of catalyzer has no particular limits, and adds 0.1 to 10 equivalent catalyst substance (boron compound) in the carboxylic group of preferred per 1 equivalent N-acylamino acid.That is to say that under situation about wherein adding less than 0.1 equivalent catalyst substance, the effect of catalyzer accelerated reaction can not obtain effect of sufficient; Under situation about wherein adding greater than 10 equivalent catalyst substances, also can not get desired unusual effect, this is because the function of catalyzer or ability are almost near saturated.
The add-on that is used as the alcohol of solubility promoter has no particular limits, and preferably adds the alcohol of 0.1 to 10 times of weight of employed B catalyst.That is to say,,, can not make fully that reaction system is a homogeneous phase under situation about wherein adding less than the alcohol of 0.1 times of weight for the reason of in this scope, using alcohol; Under situation about wherein adding, making troubles after reaction is finished, can for the processing ease that separates same solvent (alcohol) greater than the alcohol of 10 times of weight.
Heating temperature for reaction, under the situation of not using azeotropic dehydration medium (solvent), in order to remove the water that produces in the dereaction, 100 ℃ of general preferred uses or higher Heating temperature, when Heating temperature rises De Genggao, reaction can be accelerated, and in order to suppress side reaction, especially preferably uses 110 to 150 ℃ temperature.Further, under the situation that obtains optically active N-acyl amino-acid amide,, most preferably use 110 to 125 ℃ temperature in order to suppress racemization.Use carbonatoms be 8 or the situation of above amine under, preferably do not have the reaction of azeotropic dehydration medium; Under the situation of using carbonatoms less than 8 amine or ammonia, must wait device and take some skills, this is because the operability that stirs etc. can descend easily.
On the other hand, because the water that produces in the reaction can easily be removed from reaction system by component distillation, even so use carbonatoms less than 8 the situation of amine as starting raw material under, the method for carrying out reacting by heating under the condition of coexistence azeotropic dehydration medium also is suitable for.For the azeotropic dehydration medium, can not have to select under the condition that further limits any not with as the N-acylamino acid of starting raw material or the medium of amine or ammonia react.
Because after reaction is finished,, realize the washing of washing or pickling or alkaline aqueous solution easily, so carbohydrate most preferably by utilize separating the phase preparation.For the medium that is used for component distillation, needing boiling point is 98 to 150 ℃ carbohydrate.That is to say that for the reason of using this optimal temperature scope, be lower than at the carbohydrate boiling point under 98 ℃ the situation, the temperature of reaction system is too low, can not obtain enough speed of response; And be higher than under 150 ℃ of situations at the carbohydrate boiling point, reaction will not postpone (time compole short), and the side reaction that can need not is as the decomposition of N-acylamino acid, amine oxidation etc.The example that is used for the medium of azeotropic dehydration can comprise heptane, octane-iso, methylcyclohexane, suberane, tetrahydrotoluene, diisobutylene, toluene, dimethylbenzene, octane, octene, dimethyl cyclohexane, trimethyl-cyclohexane etc.When needs suppressed racemization especially, the carbohydrate that needs most boiling point and be 98 to 125 ℃ was as component distillation (dehydration) medium, and the example comprises following compound; As heptane, octane-iso, methylcyclohexane, suberane, tetrahydrotoluene, diisobutylene, toluene, octane, octene and dimethyl cyclohexane and composition thereof; By the mixture that one or more above-mentioned carbohydrate exemplary compounds of suitable mixing obtain, wherein one or more carbohydrate have high boiling point (as dimethylbenzene), then the boiling point of gained mixture can be adjusted to 125 ℃ or lower.
After reaction is finished; method for separate targets (required) N-acyl amino-acid amide; for example in reaction, do not use under the situation of azeotropic dehydration medium; can after the reaction under heating condition; product is dissolved in the organic solvent (as ethyl acetate), utilizes water or extracting and separating catalyzer such as acid or alkaline aqueous solution, unreacted starting raw material and/or side reaction product, then; under cooling conditions, the gained material is carried out recrystallization, obtain target N-acyl amino-acid amide.According to the kind of N-acyl amino-acid amide, it not only can make grease become glue in many cases, and can make organic solvent (as ethyl acetate) become glue.In this case; but owing in the time of refrigerative, can not generate crystallization and whole material agglutination; so under the pulpous state state; by utilizing water or acid or alkaline aqueous solution repetitive scrubbing reaction mixture; separable catalyzer, unreacted starting raw material and/or side reaction product (by product), thus target N-acyl amino-acid amide obtained.
Using under the situation of carbohydrate as the azeotropic dehydration medium, last what react, by fractionation by distillation azeotropic dehydration medium, can use above-described method then from organic solvent (as ethyl acetate) recrystallization.In addition; by utilizing target N-acyl amino-acid amide to be difficult to water-soluble performance; as the described method of PCT communique WO98-08806, utilize the extraction of acid extraction and/or alkali, proposition and separating catalyst, unreacted starting raw material and/or side reaction product etc.Afterwards, replace solvent, promptly utilize water to replace organic medium,, be settled out target product, be the solid particulate state by component distillation.According to described method, can obtain target (required) N-acyl amino-acid amide.
The sequence number of on October 20th, 1999 application is that the full text (the desired right of priority of the application) of 297792/1999 Japanese patent application is introduced in the present specification.
Embodiment
The present invention will explain by the following example.But the present invention also not only is confined to these embodiment.
(embodiment 1)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 52.2g boron oxide, 480g toluene, 111.1g 1-butanols and 137.2g n-Butyl Amine 99, under fluid temperature is 70 ℃ or lower condition, dropwise add 49.5g 95% sulphuric acid soln then.Then to wherein adding 267g N-lauroyl-L-sodium glutamate (" AMISOFT LS-11; Ajinomoto Co.; Inc. makes) carefully, azeotropic (azeotropic) dehydration reaction was carried out under nitrogen atmosphere 10 hours, separated the water that is generated by reflux.After confirming that by HPLC (high speed liquid chromatography) reaction is finished, in reaction soln, add 600g water, to wherein adding 18.6g 95% aqueous sulfuric acid, gained solution stirred 15 minutes down at 80 ℃, placed 10 minutes under uniform temp then.Confirm water layer pH value be 3 or littler after, the separation water layer.In remaining organic layer, add 600g 1% aqueous sulfuric acid again,, carry out the acid extraction step with above-mentioned identical method.Then, to wherein adding 600g hot water, 75g 27% aqueous sodium hydroxide solution and 27g sodium-chlor, gained solution stirred 15 minutes down at 80 ℃, placed 1 hour under uniform temp then, separated water layer.Repeating an alkali extraction step.Add 900g hot water in the residue organic layer, neutralization solution is regulated about water layer pH value to 7.Separate organic solvent by component distillation.Collect gained particulate solid material by filtering, drying under reduced pressure obtains reaction product (310g).Measure purity by HPLC, the purity of gained N-lauroyl-L-L-glutamic acid di-n-butyl acid amides is 95%.
(embodiment 2)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 143g borax, 480g toluene and 111.1g 1-butanols, dropwise add the 38.7g95% sulphuric acid soln then.Then to wherein adding 137.2g n-Butyl Amine 99 and 247g N-lauroyl-L-L-glutamic acid (" AMISOFT LS-LA " carefully; Ajinomoto Co.; Inc. make); azeotropic (azeotropic) dehydration reaction was carried out under nitrogen atmosphere 10 hours, the water that is generated by the reflux mixture separation.Last in reaction handled according to method and the operation identical with embodiment 1, obtains reaction product (317g).Measure purity by HPLC, the purity of gained N-lauroyl-L-L-glutamic acid di-n-butyl acid amides is 96%.
(embodiment 3)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 52.2g boron oxide, 247g N-lauroyl-L-L-glutamic acid (" AMISOFT LS-LA "; Ajinomoto Co.; Inc. manufacturing), 480g toluene, 125g 1-oxyethyl group-2-propyl alcohol and 137.2g n-Butyl Amine 99; azeotropic (azeotropic) dehydration reaction was carried out under nitrogen atmosphere 10 hours, the water that is generated by the reflux mixture separation.
Last in reaction carries out reaction mixture according to method and the operation identical with embodiment 1, obtains reaction product (320g).Measure purity by HPLC, the purity of gained N-lauroyl-L-L-glutamic acid di-n-butyl acid amides is 96%.
(embodiment 4)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 26.1g boron oxide, 266g N-palmitoyl-L-Xie Ansuan, 480g toluene, 55.6g1-butanols and 121g n-octyl amine; azeotropic (azeotropic) dehydration reaction was carried out under nitrogen atmosphere 9 hours, the water that is generated by the reflux mixture separation.
Last in reaction carries out reaction mixture according to method and the operation identical with embodiment 1, obtains reaction product N-palmitoyl-L-Xie Ansuan-n-octyl acid amides (318g).Measure purity by HPLC, the purity of gained N-palmitoyl-L-Xie Ansuan-n-octyl acid amides is 98%.
(embodiment 5)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 26.1g boron oxide, 260g N-lauroyl-L-phenylalanine, 62.5g 1-oxyethyl group-2-propyl alcohol and 153g dodecyl amine, be reflected under 125 ℃ and under nitrogen atmosphere, carried out 10 hours.Last what react, to wherein adding 500g hot water, 400g ethyl acetate and 9.3g 95% aqueous sulfuric acid, carry out acid extraction.Then, carry out the alkali extraction to wherein adding 500g hot water, 38g 27% aqueous sodium hydroxide solution and 13g sodium-chlor.By underpressure distillation, from the residue organic layer, separate solvent, drying under reduced pressure gained solid material obtains reaction product (343g).Measure purity by HPLC, the purity of gained N-lauroyl-L-phenylalanine dodecyl acid amides is 96%.
(embodiment 6)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 52.2g boron oxide, 235g N-palmitoyl glycine, 480g toluene, 111.1g 1-butanols and 95g di-n-propylamine; azeotropic (azeotropic) dehydration reaction was carried out under nitrogen atmosphere 18 hours, the water that is generated by the reflux mixture separation.
Last in reaction carries out reaction mixture according to method and the operation identical with embodiment 1, and the material of the liquid form that cooling obtains after removing and desolvating under agitation condition makes the particulate solid material.By filtering collection material, drying under reduced pressure obtains reaction product (267g).Measure purity by HPLC, gained N-palmitoyl glycine-N ＇, the purity of N ＇-di acid amides is 98%.
(embodiment 7)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 52.2g boron oxide, 247g N-lauroyl-L-L-glutamic acid (" AMISOFTLS-LA "; Ajinomoto Co.; Inc. manufacturing), 480g toluene, 111.1g 1-butanols and 159.7g piperidines; azeotropic dehydration is reflected at and carried out under the nitrogen atmosphere 20 hours, the water that is generated by the reflux mixture separation.
Last what react, to wherein adding 600g hot water and 200g ether,, make two-phase (two-layer) solution, phase-splitting, water phase separated then then to wherein adding 18.6g 95% aqueous sulfuric acid.In the residue organic layer, add 600g 1% aqueous sulfuric acid again, carry out the acid extraction step then.Then, repeat twice of alkali extraction step to wherein adding 600g hot water and 75g 27% aqueous sodium hydroxide solution.Utilize sodium chloride aqueous solution washing residue organic layer, utilize anhydrous sodium sulphate to remove water in the organic solvent, separate organic solvent by underpressure distillation then.Dry gained material obtains reaction product (320g).Measure purity by HPLC, the purity of gained N-lauroyl-L-L-glutamic acid dipiperidino acid amides is 95%.
(comparing embodiment 1)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 52.2g boron oxide, 247g N-lauroyl-L-L-glutamic acid (" AMISOFTLS-LA "; Ajinomoto Co.; Inc. manufacturing), 480g toluene, 137.2g n-Butyl Amine 99; azeotropic dehydration is reflected at and carried out under the nitrogen atmosphere 10 hours, the water that is generated by the reflux mixture separation.
Confirm the state that reaction is carried out by HPLC, found that principal product is one-amide derivatives, and have to two-acid amides seldom as target compound.Carry out treatment step and operation according to the method identical, until the acid extraction step with embodiment 1.By the component distillation organic solvent, drying under reduced pressure gained material obtains reaction mixture (291g).Measure purity by HPLC, the purity of gained N-lauroyl-L-L-glutamic acid di-n-butyl acid amides is 28%.
(comparing embodiment 2)
2 liters of flasks that agitator are installed, have H-shape test tube, dropping liquid instrument and a thermometer of reflux are arranged in the reactor, and the air in the reactor is substituted by nitrogen.In flask, add 52.2g boron oxide, 247g N-lauroyl-L-L-glutamic acid (" AMISOFTLS-LA "; Ajinomoto Co.; Inc. manufacturing), 480g toluene and 159.7g piperidines; azeotropic dehydration is reflected at and carried out under the nitrogen atmosphere 20 hours, the water that is generated by the reflux mixture separation.
Confirm the state that reaction is carried out by HPLC, found that principal product is one-amide derivatives, and have to two-acid amides seldom as target compound.Carry out treatment step and operation according to the method identical, until the acid extraction step with embodiment 7.Utilize sodium chloride aqueous solution washing gained organic layer, utilize the water in the anhydrous sodium sulphate removal organic solvent then, remove solvent by underpressure distillation.Dry gained material obtains reaction mixture (282g).Measure purity by HPLC, the purity of gained N-lauroyl-L-L-glutamic acid dipiperidino acid amides is 8%.
The invention effect
The present invention relates to produce the method for N-acyl amino-acid amide, the method is included in existence As at least a boron compound of catalyst and jointly have at least a as cosolvent Under the condition of alcohol, N-acylamino acid and amine and/or ammonia are carried out condensation reaction, wherein said N-octyl group amino acid can exist or exist with salt form with free form, described amine and/or ammonia Preferred primary amine, secondary amine and/or ammonia. Compare the inventive method with the method for the cosolvent that do not coexist Can obtain target product N-octyl group amino acid amide with high yield at short notice.
Claims (10)
1, a kind of N-of production acyl amino-acid amide improves one's methods; this method comprises carries out condensation reaction with N-acylamino acid or its salt and amine and/or ammonia, it is characterized in that described condensation reaction carries out under existing as the boron compound of catalyzer and the common condition that exists as the alcohol of solubility promoter.
2, according to the process of claim 1 wherein that described amine is one or more compounds that are selected from primary amine and secondary amine.
3, according to the process of claim 1 wherein that described boron compound as catalyzer is one or more compounds that are selected from ortho-boric acid, metaboric acid, pyroboric acid and boron oxide.
4, the method arbitrary, wherein said alcohol as solubility promoter according to claim 1 to 3 be contain the saturated or unsaturated fatty alcohol of the straight or branched that is selected from 3 to 8 carbon atoms, contain the saturated or unsaturated cyclic alcohol of 3 to 8 carbon atoms, one or more compounds of saturated or unsaturated alkyl ether alcohol.
5, according to the method for claim 4, wherein said saturated or unsaturated alkyl ether alcohol is at least a compound in the compound that is selected from following general formula (1) expression:
R
1-O-R
2-OH (1) is R wherein
1Expression contains the straight or branched alkyl or the unsaturated alkyl of 1 to 4 carbon atom, R
2Expression contains the straight or branched alkyl of 2 to 5 carbon atoms.
6, the method arbitrary according to claim 1 to 3, wherein said condensation reaction is carried out under 98 to 150 ℃ of temperature.
7, the method arbitrary according to claim 1 to 3, wherein said condensation reaction is carried out in one or more pure media that comprise as solubility promoter.
8, according to the method for claim 7, wherein said medium further comprises the azeotropic dehydration medium.
9, according to the method for claim 1 to 3, wherein said condensation reaction is carried out under the pickling condition.
10, a kind of method of producing N-octyl group amino acid amide; this method is included in existence as under the boron compound of catalyzer and the common condition that exists as at least a alcohol of solubility promoter, and N-acylamino acid or its salt and one or more primary amine, secondary amine and ammonia are carried out dehydration condensation.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP297792/1999 | 1999-10-20 | ||
| JP29779299 | 1999-10-20 | ||
| JP315080/2000 | 2000-10-16 | ||
| JP2000315080A JP4277438B2 (en) | 1999-10-20 | 2000-10-16 | Method for producing N-acylamino acid amide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1294121A true CN1294121A (en) | 2001-05-09 |
| CN1198795C CN1198795C (en) | 2005-04-27 |
Family
ID=26561240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001314807A Expired - Lifetime CN1198795C (en) | 1999-10-20 | 2000-10-20 | N-acyl amino-acid amide prodn. process |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1094059B1 (en) |
| JP (1) | JP4277438B2 (en) |
| KR (1) | KR100648390B1 (en) |
| CN (1) | CN1198795C (en) |
| DE (1) | DE60001787T2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307278C (en) * | 2002-06-03 | 2007-03-28 | 味之素株式会社 | Gellant |
| CN101155776B (en) * | 2005-04-07 | 2011-05-04 | 新日本理化株式会社 | Process for producing tricarboxylic acid tris(alkyl-substituted cyclohexylamide) |
| CN108912008A (en) * | 2018-06-22 | 2018-11-30 | 北京工商大学 | A method of N- fatty acid acylamino acid amide is prepared by fatty acid methyl ester |
| CN108929272A (en) * | 2018-06-22 | 2018-12-04 | 北京工商大学 | A method of with oil and fat preparation N- fatty acid acylamino acid amide |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008105945A (en) * | 2005-02-07 | 2008-05-08 | Ajinomoto Co Inc | Acylamide compound having action of promoting or inducing secretion of adiponectin |
| HU227319B1 (en) * | 2005-12-08 | 2011-03-28 | Egis Gyogyszergyar Nyrt | Process for the production of (2-chloro-ethoxy)-acetic acid-n,n-dimethylamide and its intermediate and the novel intermediate |
| JP5105297B2 (en) * | 2006-05-25 | 2012-12-26 | 味の素株式会社 | PPAR activity regulator |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6150A (en) * | 1984-02-17 | 1986-01-06 | Ajinomoto Co Inc | Production of n-acylaminoacid amide |
| DE19533010A1 (en) * | 1995-09-07 | 1997-03-13 | Hoechst Ag | Prepn. of N-acylamino di-carboxylic acid di-amide cpds. |
| DE19610323C2 (en) * | 1996-03-15 | 1998-04-16 | Hoechst Ag | Process for the preparation of N-lauroyl-L-glutamic acid di-n-butylamide |
-
2000
- 2000-10-16 JP JP2000315080A patent/JP4277438B2/en not_active Expired - Lifetime
- 2000-10-19 KR KR1020000061517A patent/KR100648390B1/en active IP Right Grant
- 2000-10-19 EP EP00309200A patent/EP1094059B1/en not_active Expired - Lifetime
- 2000-10-19 DE DE60001787T patent/DE60001787T2/en not_active Expired - Lifetime
- 2000-10-20 CN CNB001314807A patent/CN1198795C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307278C (en) * | 2002-06-03 | 2007-03-28 | 味之素株式会社 | Gellant |
| CN101155776B (en) * | 2005-04-07 | 2011-05-04 | 新日本理化株式会社 | Process for producing tricarboxylic acid tris(alkyl-substituted cyclohexylamide) |
| CN108912008A (en) * | 2018-06-22 | 2018-11-30 | 北京工商大学 | A method of N- fatty acid acylamino acid amide is prepared by fatty acid methyl ester |
| CN108929272A (en) * | 2018-06-22 | 2018-12-04 | 北京工商大学 | A method of with oil and fat preparation N- fatty acid acylamino acid amide |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010060172A (en) | 2001-07-06 |
| JP2001187769A (en) | 2001-07-10 |
| EP1094059A1 (en) | 2001-04-25 |
| DE60001787T2 (en) | 2004-02-05 |
| EP1094059B1 (en) | 2003-03-26 |
| KR100648390B1 (en) | 2006-11-24 |
| JP4277438B2 (en) | 2009-06-10 |
| DE60001787D1 (en) | 2003-04-30 |
| CN1198795C (en) | 2005-04-27 |
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